Abstract

In this article, we describe a novel Monte Carlo code for time-integrated and time-resolved photon migration simulations of excitation and fluorescent light propagation (with reabsorption) in bi-layered models of biological tissues. The code was experimentally validated using bi-layered, tissue-simulating phantoms and the agreement between simulations and experiment was better than 3%. We demonstrate the utility of the code for quantitative clinical optical diagnostics in epithelial tissues by examining design characteristics for clinically compatible waveguides with arbitrarily complex source-detector configurations. Results for human colonic tissues included a quantitative comparison of simulation predictions with time-resolved fluorescence data measured in vivo and spatio-temporal visualizations of photon migration characteristics in tissue models in both two- and three-dimensions for source-detector configurations, including variable waveguide spacing, numerical aperture, and diameter. These results were then extended from surface point spectroscopy to imaging modalities for both time-gated (fluorescence lifetime) and steady-state (fluorescence intensity) experimental conditions. To illustrate the flexibility of this computational approach, time-domain results were extended to simulate predictions for frequency-domain instrumentation. This work is the first demonstration and validation of a time-domain, multi-wavelength photon transport model with these capabilities in layered turbid-media.

© 2005 Optical Society of America

Full Article  |  PDF Article

References

  • View by:
  • |

  1. M.-A. Mycek and B.W. Pogue, eds. Handbook of biomedical fluorescence (Marcel Dekker, Inc., 2003)
  2. F. Koenig, F. Mcgovern, A. Althausesn, T. Deutsch, and K. Schomacker, "Laser induced autofluorescence diagnosis of bladder cancer," J. Urol. 156, 1597-1602 (1996)
    [CrossRef] [PubMed]
  3. M.-A. Mycek, K. Schomacker, and N. Nishioka, "Colonic polyp differentiation using time resolved autofluorescence spectroscopy," Gastrointestinal Endoscopy 48, 390-394 (1998)
    [CrossRef] [PubMed]
  4. K.T. Schomacker, J.K. Frisoli, C.C. Compton, T.J. Flotte, J.M. Richter, N.S. Nishioka, and T.F. Deutsch, "Ultraviolet laser-induced fluorescence of colonic tissue: Basic biology and diagnostic potential," Lasers Surg. Med. 12, 63-78 (1992)
    [CrossRef] [PubMed]
  5. N. Ramanujam, A. Mahadevan, M. Follen-Mitchell, S. Thomsen, E. Silva, and R. Richards-Kortum, "Fluorescence spectroscopy of the cervix," Clinical Consultations in Obstetrics and Gynecology 6, 62-69 (1994)
  6. S. Lam, C.J. Macaulay, C. Leriche, N. Ikeda, and B. Palcic, "Early localization of bronchogenic carcinoma," Diagnostic and Therapeutic Endoscopy 1, 75-78 (1994)
    [CrossRef] [PubMed]
  7. H. Yokomise, K. Yanagihara, T. Fukuse, T. Hirata, O. Ike, H. Mizuno, H. Wada, and S. Hitomi, "Clinical experience with lung-imaging fluorescence endoscope (life) in patients with lung cancer," J. Bronchology 4, 205-208 (1997)
    [CrossRef]
  8. T.D. Wang, J. Van-Dam, J.M. Crawford, E.A. Preisinger, Y. Wang, and M.S. Feld, "Fluorescence endoscopic imaging of human colonic adenomas," Gastroenterology 111, 1182-1191 (1996)
    [CrossRef] [PubMed]
  9. B. Chwirot, S. Chwirot, W. Jedrzejczyk, M. Jackowski, A. Raczynska, J. Winczakiewicz, and J. Dobber, "Ultraviolet laser-induced fluorescence of human stomach tissues: Detection of cancer tissues by imaging techniques," Lasers Surg. Med. 21, 149-158 (1997)
    [CrossRef] [PubMed]
  10. R.S. Dacosta, B.C. Wilson, and N.E. Marcon, "Light-induced fluorescence endoscopy of the gastrointestinal tract," Gastrointestinal Endoscopy 10, 37-69 (2000)
  11. H. Zeng, C. Macaulay, D.I. Mclean, and B. Palcic, "Reconstruction of in vivo skin autofluorescence spectrum from microscopic properties by monte carlo simulation," J. Photochem. Photobiol. 38, 234-240 (1997)
    [CrossRef]
  12. K. Rinzema, L.H.P. Murrer, and W.M. Star, "Direct experimental verification of light transport theory in an optical phantom," J. Opt. Soc. Am. A 15, 2078-2088 (1998)
    [CrossRef]
  13. K. Vishwanath, B.W. Pogue, and M.-A. Mycek, "Quantitative fluorescence lifetime spectroscopy in turbid media: Comparison of theoretical, experimental and computational methods," Phys. Med. Biol. 47, 3387-3405 (2002)
    [CrossRef] [PubMed]
  14. D. Hidovic-Rowe and E. Claridge, "Modeling and validation of spectral reflectance for the colon," Phys. Med. Biol. 50, 1071-1093 (2005)
    [CrossRef] [PubMed]
  15. A.J. Welch and M.J.C. Van-Gemert, Optical-thermal response of laser-irradiated tissue (Plenum Press, New York, 1995)
  16. K. Vishwanath, "Computational modeling of time-resolved fluorescence transport in turbid media for noninvasive clinical diagnostics," Ph.D. (University of Michigan, Ann Arbor, 2005)
  17. L. Wang, S.L. Jacques, and L. Zheng, "Mcml - monte carlo modeling of photon transport in multi-layered tissues," Comput Methods Programs Biomed 47, 131-146 (1995)
    [CrossRef] [PubMed]
  18. S.L. Jacques, "Time resolved propagation of ultrashort laser pulses within turbid tissue," Appl. Opt. 28, 2223-2229 (1989)
    [CrossRef] [PubMed]
  19. B.W. Pogue and G. Burke, "Fiber-optic bundle design for quantitative fluorescence measurement from tissue," Appl. Opt. 37, 7429 - 7436 (1998)
    [CrossRef]
  20. K. Vishwanath and M.-A. Mycek, "Do fluorescence decays remitted from tissues accurately reflect intrinsic fluorophore lifetimes?," Opt. Lett. 29, 1512-1514 (2004)
    [CrossRef] [PubMed]
  21. J. Valenzuela, K. Vishwanath, and M.-A. Mycek, "Designing optical waveguides for clinical diagnostics in layered tissues: Experimental testing with tissue phantoms," in IEEE Conference on Lasers and Electro-Optics (LEOS), 1, 827-829 (2004)
  22. A. Sefkow, M. Bree, and M.-A. Mycek, "A method for measuring cellular optical absorption and scattering evaluated using dilute cell suspension phantoms," Appl. Spectrosc. 55, 1495-1501 (2001)
    [CrossRef]
  23. J.D. Pitts and M.-A. Mycek, "Design and development of a rapid acquisition laser-based fluorometer with simultaneous spectral and temporal resolution," Rev. Sci. Instrum. 72, 3061-3072 (2001)
    [CrossRef]
  24. T.J. Pfefer, L.S. Matchette, A.M. Ross, and M.N. Ediger, "Selective detection of fluorophore layers in turbid media: The role of fiber-optic probe design," Opt. Lett. 28, 120-122 (2003)
    [CrossRef] [PubMed]
  25. E. Kuwana and E.M. Sevick-Muraca, "Fluorescence lifetime spectroscopy in multiply scattering media with dyes exhibiting multiexponential decay kinetics," Biophys. J. 83, 1165-1176 (2002)
    [CrossRef] [PubMed]

Appl. Opt. (2)

Appl. Spectrosc. (1)

Biophys. J. (1)

E. Kuwana and E.M. Sevick-Muraca, "Fluorescence lifetime spectroscopy in multiply scattering media with dyes exhibiting multiexponential decay kinetics," Biophys. J. 83, 1165-1176 (2002)
[CrossRef] [PubMed]

CLEO 2004 (1)

J. Valenzuela, K. Vishwanath, and M.-A. Mycek, "Designing optical waveguides for clinical diagnostics in layered tissues: Experimental testing with tissue phantoms," in IEEE Conference on Lasers and Electro-Optics (LEOS), 1, 827-829 (2004)

Clin. Consult. in OB/GYN (1)

N. Ramanujam, A. Mahadevan, M. Follen-Mitchell, S. Thomsen, E. Silva, and R. Richards-Kortum, "Fluorescence spectroscopy of the cervix," Clinical Consultations in Obstetrics and Gynecology 6, 62-69 (1994)

Comput Methods Programs Biomed (1)

L. Wang, S.L. Jacques, and L. Zheng, "Mcml - monte carlo modeling of photon transport in multi-layered tissues," Comput Methods Programs Biomed 47, 131-146 (1995)
[CrossRef] [PubMed]

Diagnostic and Therapeutic Endoscopy (1)

S. Lam, C.J. Macaulay, C. Leriche, N. Ikeda, and B. Palcic, "Early localization of bronchogenic carcinoma," Diagnostic and Therapeutic Endoscopy 1, 75-78 (1994)
[CrossRef] [PubMed]

Gastroenterology (1)

T.D. Wang, J. Van-Dam, J.M. Crawford, E.A. Preisinger, Y. Wang, and M.S. Feld, "Fluorescence endoscopic imaging of human colonic adenomas," Gastroenterology 111, 1182-1191 (1996)
[CrossRef] [PubMed]

Gastrointestinal Endoscopy (2)

M.-A. Mycek, K. Schomacker, and N. Nishioka, "Colonic polyp differentiation using time resolved autofluorescence spectroscopy," Gastrointestinal Endoscopy 48, 390-394 (1998)
[CrossRef] [PubMed]

R.S. Dacosta, B.C. Wilson, and N.E. Marcon, "Light-induced fluorescence endoscopy of the gastrointestinal tract," Gastrointestinal Endoscopy 10, 37-69 (2000)

J. Bronchology (1)

H. Yokomise, K. Yanagihara, T. Fukuse, T. Hirata, O. Ike, H. Mizuno, H. Wada, and S. Hitomi, "Clinical experience with lung-imaging fluorescence endoscope (life) in patients with lung cancer," J. Bronchology 4, 205-208 (1997)
[CrossRef]

J. Opt. Soc. Am. A (1)

J. Photochem. Photobiol. (1)

H. Zeng, C. Macaulay, D.I. Mclean, and B. Palcic, "Reconstruction of in vivo skin autofluorescence spectrum from microscopic properties by monte carlo simulation," J. Photochem. Photobiol. 38, 234-240 (1997)
[CrossRef]

J. Urol. (1)

F. Koenig, F. Mcgovern, A. Althausesn, T. Deutsch, and K. Schomacker, "Laser induced autofluorescence diagnosis of bladder cancer," J. Urol. 156, 1597-1602 (1996)
[CrossRef] [PubMed]

Lasers Surg. Med. (2)

K.T. Schomacker, J.K. Frisoli, C.C. Compton, T.J. Flotte, J.M. Richter, N.S. Nishioka, and T.F. Deutsch, "Ultraviolet laser-induced fluorescence of colonic tissue: Basic biology and diagnostic potential," Lasers Surg. Med. 12, 63-78 (1992)
[CrossRef] [PubMed]

B. Chwirot, S. Chwirot, W. Jedrzejczyk, M. Jackowski, A. Raczynska, J. Winczakiewicz, and J. Dobber, "Ultraviolet laser-induced fluorescence of human stomach tissues: Detection of cancer tissues by imaging techniques," Lasers Surg. Med. 21, 149-158 (1997)
[CrossRef] [PubMed]

Opt. Lett. (2)

Phys. Med. Biol. (2)

K. Vishwanath, B.W. Pogue, and M.-A. Mycek, "Quantitative fluorescence lifetime spectroscopy in turbid media: Comparison of theoretical, experimental and computational methods," Phys. Med. Biol. 47, 3387-3405 (2002)
[CrossRef] [PubMed]

D. Hidovic-Rowe and E. Claridge, "Modeling and validation of spectral reflectance for the colon," Phys. Med. Biol. 50, 1071-1093 (2005)
[CrossRef] [PubMed]

Rev. Sci. Instrum. (1)

J.D. Pitts and M.-A. Mycek, "Design and development of a rapid acquisition laser-based fluorometer with simultaneous spectral and temporal resolution," Rev. Sci. Instrum. 72, 3061-3072 (2001)
[CrossRef]

Other (3)

A.J. Welch and M.J.C. Van-Gemert, Optical-thermal response of laser-irradiated tissue (Plenum Press, New York, 1995)

K. Vishwanath, "Computational modeling of time-resolved fluorescence transport in turbid media for noninvasive clinical diagnostics," Ph.D. (University of Michigan, Ann Arbor, 2005)

M.-A. Mycek and B.W. Pogue, eds. Handbook of biomedical fluorescence (Marcel Dekker, Inc., 2003)

Supplementary Material (2)

» Media 1: GIF (2272 KB)     
» Media 2: GIF (2370 KB)     

Cited By

OSA participates in CrossRef's Cited-By Linking service. Citing articles from OSA journals and other participating publishers are listed here.

Alert me when this article is cited.


Figures (9)

Fig. 1.
Fig. 1.

Apparatus used for accurate control of fiber-optic source-detector positioning relative to the surface of the bi-layered phantom (cylindrical layers at center).

Fig. 2.
Fig. 2.

(a) shows reference normalized (see text) fluorescence emission spectra of fluorophores POPOP in DI H2O and Rhodamine-6G in RTV-141. (b) shows variations in the fluorescence emission spectra from the bi-layered tissue phantom (Tissue #1, Table 1) for different source-detector separations ρ.

Fig. 3.
Fig. 3.

(a) shows a schematic of the compound probe used in simulations (the central fiber is the source fiber). (b) and (c) depict cross-sectional views of the model tissue (Tissue #3, Table 1). The downward arrow indicates the source, while the upward arrows indicate the detectors. (d) shows the calculated fractional fluorescence contribution detected from each layer vs. ρ (as described in the text)

Fig. 4.
Fig. 4.

Comparisons of the experiments (circles) with simulations (triangles) for the bi-layered tissue phantoms listed in Table 1. Fig. 4(a)–4(d) correspond to Tissue#1 -Tissue #4, respectively. In each figure, blue lines indicate fractional fluorescence contributions from the top layer, while red lines show contributions from the bottom layer.

Fig. 5.
Fig. 5.

Time-resolved fluorescence decays measured in vivo are shown in (a), while computational simulations are shown in (b). Normal tissues are indicated by the solid blue lines, while pre-cancerous adenomatous tissues are shown by the red dashed lines.

Fig. 6.
Fig. 6.

(a)-(c) show the projected 2-d map of fluorescence photons reaching the detector for varying detector numerical apertures, while (e)-(f) show that for varying detector diameters d (see text). Figs. (d) and (h) quantify these data as fractional fluorescence contributions vs. source-detector separation ρ for the top layer (blue lines) and the bottom layer (red lines). These simulations modeled normal human colon tissue (CTM1, Table 2).

Fig. 7.
Fig. 7.

For the normal colon tissue model (CTM1), 3-dimensional visualizations showing the spatial origins of fluorescence photons reaching the detectors (orange tubes). The excitation was delivered via a source-fiber (blue tube). (a) and (c) show time-gated snapshots (between 1.1- 1.2 ns), while (b) and (d) show time-integrated data. The multimedia movie shows the data from 0-6 ns (2.21MB).

Fig. 8.
Fig. 8.

Surface fluorescence intensity maps showing the remitted tissue fluorescence for the two simulated colon tissue models in Table 2. (a) shows the surface of a normal tissue (CTM1), while (b) shows that of an adenomatous tissue (CTM2). The multimedia movie shows the data from 0-6 ns (2.31MB).

Fig. 9.
Fig. 9.

Equivalence of analyzing fractional fluorescence contributions for a bi-layered normal colon tissue model (CTM1, Table 2) via steady-state (circles), time-resolved (crosses), or frequency-domain (diamonds) techniques. Blue lines show fractional contributions from the fluorophore in layer 1, while the red lines show that from the fluorophore in layer 2.

Tables (2)

Tables Icon

Table 1. Differences in the four bi-layered tissue models used to validate the simulations.

Tables Icon

Table 2. Parameters used in normal (CTM1) and pre-cancerous (CTM2) human tissue models in Section 4. The anisotropy coefficients of both layers were fixed at 0.9 for all simulations.

Metrics